Neuropathic pain results from injury to a nerve rather than injury to a tissue. Pain from tissue injury is typically short lived and is usually limited to the period of tissue repair. This pain can be readily treated by any of a number of over the counter and prescription analgesics well known to those skilled in the art. In contrast, neuropathic pain can develop days or even months after traumatic nerve injury and the pain is typically long-lasting or chronic. Moreover, neuropathic pain can occur spontaneously or as a result of stimulation that is normally not painful.
Neuropathic pain is caused by both trauma and disease. For example, trauma nerve compression or crush and traumatic injury to the spinal cord or brain are common causes. During nerve healing and regeneration, neuromas can result in pain due to abnormal nerve regeneration. Nerve crush and compression can be caused by the growth of tumors or other abnormalities, resulting in pain. Additionally, neuropathies may be caused by a number of diseases and disease conditions including diabetes mellitus, chemotherapy treated cancer, post herpetic neuralgia, lumbar radiculopathy, ischemia, vasculitis, alcoholism, HIV and some vitamin deficiencies.
Neuropathic pain is not readily treatable by common analgesics. Current therapies typically have severe side effects including, for example, cognitive changes, sedation, nausea and, with narcotic drugs, addiction. As neuropathic pain is frequently related to other disease states, individuals may suffer from adverse drug interactions or be less able to tolerate the side effects of the drugs. These limitations in current therapies can result in depression and a decreased quality of life in those suffering from neuropathic pain.
After nerve injury, peripheral nerves begin to degenerate, starting at the site of injury and progressing to the nerve terminal. This process, Wallerian degeneration, is essential for regeneration and has been characterized extensively in an animal model of neuropathic pain, chronic constriction injury (CCI). During degeneration, the axoplasm gradually disintegrates and the axolemma fragments. Schwann cells and macrophages phagocytose myelin debris. This process activates a secretion of a series of known and unknown factors including interferons, tumor necrosis factor-alpha (TNF-α), nerve growth factor (NGF) and interleukins. These agents directly influence the structure and function of both adjacent and distal tissue, including the induction of apoptosis in a number of peripheral cells and production of trophic factors required for regeneration of both nerve and peripheral cells.
Development of increased sensitivity to noxious stimuli (hyperalgesia) in nerve injured animals arises from a complex series of events. These include: 1) early electrophysiological events like “injury discharge” that alters neuronal influx of calcium to activate kinases such as protein kinase A and C, and the extracellular regulated kinases (ERK 1/2), leading to proliferation, chemotaxis and other cellular activation at the injury site and physiological changes at the cell body; and 2) intermediate events such as retrogradely transported injury signals that include target derived factors/cytokines. These events can occur from hours to weeks after nerve injury resulting in pain and hypersensitivity for the duration of the process. Studies using axoplasm extruded from injured ends of axons and injected into the cell bodies of uninjured sensory neurons found that the axoplasm elicited the same increase in excitability a day later in the uninjured neurons as those produced by axonal injury. In contrast, axoplasm from uninjured neurons had no effect, demonstrating expression and/or activation of factors in the injured nerve.
Studies have demonstrated that the factors secreted and activated by injured nerves and peripheral cells are responsible for the establishment of neuropathic pain. Trophic factors such as NGF and TNF-α are produced by Schwann cells and invading macrophages after nerve injury and are correlated with onset of hyperalgesia. Interestingly, both of these factors also have positive regenerative effects on damaged nerves, but cause pain in both undamaged and damaged nerves and result in thermal hyperalgesia and mechanical allodynia in non-injured animals. Similar responses are seen in humans. NGF induces changes in phenotype of sensory neurons by upregulating growth related molecules which may lead to hyperinnervation and amplifying sensory input by increasing neuropeptide levels. One key neuropeptide is substance P, which elicits pain through the neurokinin receptor (NK-1) receptor. NGF can induce the release of substance P which is known to be released in through activation of an unknown tyrosine kinase pathway which is likely mediated by cytokine-induced signaling. These complex and redundant pleiotrophic signaling pathways make the treatment of neuropathic pain, without the inhibition of neuronal healing, a substantial challenge.